Monoclonal antibodies can be used as carriers of radionuclides for tumor imaging and therapy. At present, all therapeutic trials directed at selectively destroying tumors have utilized I-131 as the radionuclide while I-123, I-131, In-111 and Ta-99 m have been coupled with monoclonal antibodies for immunoscintigraphy studies. The approach of using a monoclonal antibody to carry a radionuclide useful in therapy is most beneficial for the treatment of tumors not easily amenable to surgical control, as well as for treatment of early recurrence and of distant metastases. Among the factors that determine if a specific tumor can be destroyed following this technique are the various chemical and biological factors which can influence antibody specificity, stability and kinetics, as well as dosimetric considerations for effective therapy. The choice of the radiolabel is an equally important factor that needs to be optimized to allow the modality to fulfill its potential. I-131 has been used in the therapeutic trials to date because of its ready availability at moderate cost, the ease of halogenation techniques for proteins, and its long history of use in treating thyroid malignancy; these factors do not necessarily signify that it is a prime candidate for use in radioimmunotherapy.
When selecting the radionuclide to be carried by the monoclonal antibdy for radioimmunotherapy applications, the important physical variables include the radionuclide half-life, the type, energy and branching ratio of particulate radiation, and the gamma-ray energies and abundances. It is important to match the physical half-like of the radionuclide with the antibody's in vivo pharmacokinetics. If the half-life is too short, most decay will have occurred before the monoclonal antibody has reached maximum tumor/background ratio. Conversely, if the half-life is too long, this results in unwanted radiation dose to other healthy tissues after the labeled monoclonal antibody is shed from the tumor. It is important to consider the type of particulate emission. Auger and low-energy conversion electrons are potently lethal due to direct ionization and molecular disruption following induced Coulomb explosions. However, this effect can only be realized with intranuclear localization of the radionuclide because of very short range of the particles. Alpha particles have a high linear energy transfer (LET) which is effective in cell killing, but only in a range of several cell diameters. Beta particles are less densely ionizing and have longer range than alphas so that the distribution requirements are less restrictive for radioimmunotherapy. The gamma-ray energies and abundances are also important physical properties because the presence of gamma rays offers the possibility of external imaging but also adds to the whole body dose.
The main chemical variables to be considered in choosing a radionuclide for therapy with monoclonal antibodies are the radionuclide specific activity achievable, metal-ion contamination, the number of labels per monoclonal antibody molecule obtainable without loss of immunological activity, and the stability of the radionuclide-protein bond.
These physical and chemical factors must be viewed in light of available biological information which shows variation in antibody uptake, macro and microdistribution, and kinetics depending on the particular antibody, the variability of antigenic expression in the tumor, its size and stage. Antibodies usually require 1-3 days to reach maximum target to non-target uptake ratios, with residence times on the tumor ranging between 0.5 and 3 days. It is thus most advantageous to use an intermediate half-life radionuclide to match the uptake process and residence time of the monoclonal antibody. Thus the eight day half-life of I-131 is too long for optimum radioimmunotherapy. Also, it is well known that deiodination occurs in vivo so that the radionuclide separates from the antibody carrier. Although there may be numerous antigen sites per tumor cell, present evidence indicates a heterogeneous distribution of the monoclonal antibody in most cases. This fact reduces the attractiveness of short-ranged alpha or Auger emitters as radiolabels for antibodies. It is desirable to deliver ionizing radiation with a range close to 1 mm in tissue, as from intermediate to high energy beta particles in order to effect a uniform tumor dose even if the antibody deposition on the tumor is not uniform.
The number of viable candidate radionuclides having both the desired high beta energy and half-life comparable to antibody uptake kinetics is limited by an inverse relationship between half-life and beta decay energy. Therefore, there are only a few radionuclides that have both the desired high beta energy and a several-day half-life. The present invention presents a new approach to radioimmunotherapy that overcomes this restriction of the prior art. This new approach involves labeling monoclonal antibodies with intermediate half-life radionuclides which decay to much shorter half-life daughters with high-energy beta emissions. Since the daughter is in equilibrium with the parent, it can exert an in-situ tumoricidal effect over a prolonged period in a localized fashion, essentially as an "in vivo generator".